We have used rat hippocampus as a model to study the synaptic locations of 3H-imipramine and 3H-mianserin binding sites and role in the therapeutic action of antidepressants. Degeneration of 5HT terminals with 5,7-dihydroxytryptamine (5,7-DHT) lesion or fimbria-fornix transection led to a decrease in imipramine binding sites but an increase in mianserin binding sites. Lesion with kainic acid decreased the binding sites for mianserin without affecting the binding for imipramine. Hence the majority of imipramine binding sites are located presynaptically while most of the mianserin sites are present postsynaptically in the 5HT synapses. Lesions of 5-HT terminals abolished the down-regulation of Beta-adrenergic receptors in the hippocampal membranes of rats treated chronically with imipramine or desipramine. Thus an interneuronal system connecting the axons of 5-HT and NE neurons is operating during imipramine-induced Beta-receptor down-regulation. Following chronic treatments with imipramine or desipramine, the density of imipramine binding sites was decreased and the uptake of 3H-5HT in the hippocampal slices was facilitated. The disinhibition of the uptake may modify the synaptic function of the interneuron, resulting in down-regulation of Beta-adrenergic receptors and relief of depression symptoms.